The mechanism of water-gas shift reaction at the three-phase boundary of Pt/CeO2 catalysts has been investigated using density functional theory and microkinetic modeling to better understand the importance of metal-oxide interface sites in heterogeneous catalysis. Analysis of a microkinetic model based on parameters obtained from first principles suggests that both the "Redox pathway" and the "Associative carboxyl pathway with redox regeneration" could operate on Pt/CeO2 catalysts. Although (I) only few interfacial Pt atoms are found to be catalytically active at low temperatures due to strong adsorption of CO and (2) interfacial O-H bond breakage is difficult due to the high reducibility of ceria, interface sites are 2-3 orders of magnitude more active than Pt (111) and stepped Pt surface sites and therefore effectively determine the overall activity of Pt/CeO2. The high activity of Pt/CeO2 interface sites originates from a significantly enhanced water activation and dissociation at interfacial oxygen vacancies. (C) 2013 Elsevier Inc. All rights reserved.